Rational Targeting of Cellular Cholesterol in Diffuse Large B-Cell Lymphoma (DLBCL) Enabled by Functional Lipoprotein Nanoparticles: A Therapeutic Strategy Dependent on Cell of Origin
| Autor: | Sol Misener, C. Shad Thaxton, Kaylin M. McMahon, Richard Longnecker, Osman Cen, Tim Taxter, Leo I. Gordon, Jonathan S. Rink, Amir Behdad, Shuo Yang |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Receptors Antigen B-Cell Pharmaceutical Science Antineoplastic Agents Apoptosis Biology Article 03 medical and health sciences chemistry.chemical_compound immune system diseases hemic and lymphatic diseases Drug Discovery medicine Humans Scavenger receptor Receptor Receptors Lipoprotein Cholesterol breakpoint cluster region Germinal center Scavenger Receptors Class B medicine.disease SCARB1 030104 developmental biology Biochemistry chemistry Cancer cell Cancer research Nanoparticles Molecular Medicine lipids (amino acids peptides and proteins) Lymphoma Large B-Cell Diffuse Lipoproteins HDL Diffuse large B-cell lymphoma Signal Transduction |
| Zdroj: | Molecular Pharmaceutics. 14:4042-4051 |
| ISSN: | 1543-8392 1543-8384 |
| DOI: | 10.1021/acs.molpharmaceut.7b00710 |
| Popis: | Cancer cells have altered metabolism and, in some cases, an increased demand for cholesterol. It is important to identify novel, rational treatments based on biology, and cellular cholesterol metabolism as a potential target for cancer is an innovative approach. Toward this end, we focused on diffuse large B-cell lymphoma (DLBCL) as a model because there is differential cholesterol biosynthesis driven by B-cell receptor (BCR) signaling in germinal center (GC) versus activated B-cell (ABC) DLBCL. To specifically target cellular cholesterol homeostasis, we employed high-density lipoprotein-like nanoparticles (HDL NP) that can generally reduce cellular cholesterol by targeting and blocking cholesterol uptake through the high-affinity HDL receptor, scavenger receptor type B-1 (SCARB1). As we previously reported, GC DLBCL are exquisitely sensitive to HDL NP as monotherapy, while ABC DLBCL are less sensitive. Herein, we report that enhanced BCR signaling and resultant de novo cholesterol synthesis in ABC DLBCL drastically reduces the ability of HDL NPs to reduce cellular cholesterol and induce cell death. Therefore, we combined HDL NP with the BCR signaling inhibitor ibrutinib and the SYK inhibitor R406. By targeting both cellular cholesterol uptake and BCR-associated de novo cholesterol synthesis, we achieved cellular cholesterol reduction and induced apoptosis in otherwise resistant ABC DLBCL cell lines. These results in lymphoma demonstrate that reduction of cellular cholesterol is a powerful mechanism to induce apoptosis. Cells rich in cholesterol require HDL NP therapy to reduce uptake and molecularly targeted agents that inhibit upstream pathways that stimulate de novo cholesterol synthesis, thus, providing a new paradigm for rationally targeting cholesterol metabolism as therapy for cancer. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|